19-substituted pregnenes



United States Patent 3,206,458 Iii-SUBSTITUTED PREGNENES Albert Bowers, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed June 12, 1962, Ser. No. 201,765 14 Claims. (Cl. 260-23955) The present invention relates to novel cyclopentano phenanthrene derivatives and to a process for the production thereof. a

More particularly, the present invention relates to novel 19-lower alky1-19-hydroxy and 19-lower alkyl-19-keto- A -pregnene-3fl-ol derivatives.

The novel compounds of the present invention are represented by the following formulae:

CH CH In the above formulae R represents hydrogen, hydroxyl or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T represents hydrogen, a-hydroxy, at-

, 3,205,458 Patented Sept. 14, 1965 acyloxy, u-methyl or ,B-methyl; T and R together represent the group "Ice at the 16u,17a-position, wherein R and R each represents a lower alkyl group; X represents a lower alkyl group and R and R represent hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

The acyloxy and acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, or aromatic, and may be substituted by functional groups such as hydroxy, alkoXy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and SI-chloropropionate.

The compounds represented by the above formulae are powerful progestational agents with good oral activity. In addition they have anti-androgenic, anti-gonadotrophic and anti-estrogenic properties and are very useful in fertility control. Furthermore, they may be used in the treatment of premenstrual tension and exhibit blood :cholesterol lowering and diuretic activities.

The novel compounds of the present invention are prepared by the process exemplified as follows:

In the above formulae R, R R T and X have the drogen or a hydroxyl group; T may be hydrogen, a-rnethyl or fi-rnethyl; R and T together, and R and T together,

wherein R and R have the same meaning as set forth hereinbefore. Ac represents the acyl group of a hydrocarbon carboxylic acid of the type described hereinabove.

In practicing the process outlined above, the starting Compound I, which is a A pregnene-3p,19-diol-20-one,

preferably the S-acetate, is treated with ethylene glycol in the presence of p-toluenesulfonic acid, thus affording the ZO-cycloethylenedioxy derivative of the corresponding compound. This 20-cycloethylenedioxy derivative is then oxidized, preferably with chromium trioxide in pyridine, thus affording the corresponding 20-cycloethylenedioxy- A -pregnen-3fl-ol-l9-al acetate (11). The acetoxy group of the latter compound is hydrolyzed conventionally in a basic medium to afford the corresponding free Sfi-alcohol, which upon reaction with dihydropyrane in the presence of p-toluenesulfonic acid under strictly anhydrous conditions, yields the 3-tetrahydropyranyletl1er of the corresponding 20 cycloethylenedioxy A -pregnen-3fi-ol-19-al (III). The latter derivative, upon treatment with a lower alkyl magnesium halide such as methyl magnesium bromide or ethyl magnesium bromide, yields the 3-tetrahydropyranyl-ether of the corresponding 20-cycloethylenedioxy- 19-lower alkyl-A -pregnene-3BJ9diol '(IV), with the hydrolysis of any existing iacyloxy groups in the starting compound taking place concurrently, as for example, a 17a-acyloxy derivative is hydrolyzed to the 17a-hydroxyl compound. The free 19-hydroxyl group of the latter compound is oxidized, in a neutral or slightly basic medium,

preferably with chromium trioxide in pyridine, to give the B-tetrahydropyranylether of the corresponding 20- cycloethylenedioxy 19-lower alkyl-A -pregnen-3 5-01-19- one (VI). The 3-tetrahydropyranylether and 2-0-cycloethylenedi-oxy groupings of the 19-lower alkyl compounds described hereinbefore are conventionally hydrolyzed in an acid medium to give the corresponding 3B-hydroxy-20- keto-A -pregnene derivatives (V, VII).

The compounds of the present invention having a 16a, 17oc,ket0llld6 grouping yield the corresponding 1 6u,17adi-ols by conventional treatment with a strong organic acid such as formic acid.

The second hydroxyl groups of the compounds described in the present invention such as the 3, 1-9 or 16- hydroxyl groups, are conventionally acylated in pyridine with an acylating agent such as an anhydride or a chloride of a hydrocarbon carboxylic acid of the type disclosed bereinbefore to give'the corresponding acylates.

The tertiary hydroxyl group of the compounds of the present invention, namely, at C-1706, is conventionally esterified in the presence of p-toluenesulfonic acid with tan acylating agent, as for example, acetic anhydride or caproic anhydride, thusaffording the corresponding 17aacyloxy derivatives.

The followingspecific examples. serve to illustrate but are not intended to limit the scope of the present invention:

2 Example I A mixture of .10 g. of 16 8-rnethyl-A pregnene-3B,17a, 19-triol-20-one 3,17-diacet-ate (obtained in accordance with my U.S. patent application on Serial No. 194,717, filed May 14, 1962, now U.S. Patent No. 3,124,574 by reacting 16/3-methyl-pregnenolone with acetic anhydride and p-toluenesulfonic acid to produce 35,20-diacetoxyl6/3-met-hyl-A -pregnadiene which 'upon peracid oxidation is converted into the 35,20,6-diacetoxy-16B-methyl- 5a,6a,17a,20a-bis-oxido-pregnane. Upon treatment of the latter with dilute methanolic potassium hydroxide, there is formed the 16,6-methyl-5a,6u-oxido-pregnane-3 3,17adiol 20-one '3-acetate which is reacted with zinc in acetic acid to form 16fl methyl-A -pregnene-3,8,17a-diol-20-one 3-acetate and further esten'fied with acetic anhydride to produce 16B-methyl-A -pregnen-3B;17a-diol-20-one diacctate. The latter compound is converted into loo-methyl- A pregnene-3/i,17-a, 19-triol 20-one 3,17-diacetate by the method disclosed in my copending application Serial No. 194,716, filed May -14, 1962, now U.S. Patent No. 3,065,228), 250 cc. of dry benzene, 50 cc. of ethylene glycol and 500 mg. of p-toluenesulfonic acid monohydrate was refluxed for 16 hours using a water separator. It was then washed with a sodium bicarbonate solution, water and subsequently dried and evaporated to dryness. Recrystallization from acetone-hexane yielded ZO-cycloethylenedioxy-l6 8-methyl-A -pregnene-3e,l7e,19-triol 3,17-diacetate (Compound No. 1).

Following the same procedure, the starting compounds listed under I (obtained in accordance with my U.S. patent application Ser. No. 194,716, filed May 14, 1962, now U.S. Patent No. 3,065,228) were converted into the corresponding compounds set forth under 11.

I Cpd.

pregnene-3fl,19-diol S-acetate.

di01-20-one 3-acetate. methyl-M-pregnene-Iifl,l9-

diol 3acetate.

A -pregnene-3 B,17a,19-trio1 3,17-diacetate (Compound No. 1) in cc. of pyridine was added to a mixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reaction mixture was kept :at room temperature overnight. It was then diluted with ethyl acetate, filtered through celite and the filtrate washed with water, dried and evaporated to dryness. Crystallization from acetone-hexane afforded 20 cycloethylenedioxy-16fi-methyl-A -pregnene- 3fl-,17a-d.iol-19-al diacetate (Cpd. No. 8).

The Compounds Nos. 2 to 7, inclusive, were treated in accordance with the above procedure, thus yielding respectively:

9. 20-cycloethylenedioxy-A -pregnen-3,B-ol-l9-a1 acetate 10. 20-cycloethylenedioxy-16a-methyl-A -pregnen- 35-01-19-al acetate 11. 20.-cycloethylenedioxy-16B-methy1-A -pregnen- 12; ZO-cycloethylenedioxy-l6u,17a-isopropylidenedioxy-A 1pregnen-3 8-ol-19-alacetate 13. 2O-cycloethylenedioxy-A -pregnene-3,8,17u-diol- 19-a1 3,17-diaceta-te 14. 20-cycloethylenedioxy-l6a-methyl-A -pregnene- 1 3,6,17a-diol-19-al 3,17-diacetate Example 3 2 g. of Compound No. 8 Was dissolved in 50 cc. of methanol and treated with 5 cc. of a 4% aqueous solution of potassium hydroxide; the reaction mixture was stirred for 1 hour under an atmosphere of nitrogen at C.; the mixture was neutralized with acetic acid and the methanol distilled under reduced pressure. The residue was triturated with water and the solid collected, Washed with water, dried and recrystallized from ethyl acetate-methanol, thus producing 20-cycloethylenedioxy- 16B methyl A pregnene-3fi,l7ocdiol-l9-al l7-acetate (Compound No.

By the same procedure, the Compounds Nos. 9 to 14, inclusive, were respectively converted into:

Cpd. No.

v 16. -cycloethylenedioxy-A -pregnen-3,8-ol-19-al 17. 20-cycloethylenedioxy-l6a-methyl-A -pregnen- 3,8 ol-19 'al 18. 20-cycloethylenedioxy-16fl-methyl-A -pregnen- -01-19-211 19. 20-cycloethylenedioxy-16u,17a-isopropy1idenedioxy-M-pregnen-Bfiol-19-al 20. 20-cycloethylened-ioxy-A -pregnene-3f3,17a-dio1- 19-al 17-acetate 21. 20-cycloethylenedioxy-16a-methylA -pregnene 3 3,17a-diol-19-al 17-acetate Example 4 2 cc. of dihydropyrane were added to a solution of l 'g. of ZO-cycloethylenedioxy-l6B-methyl-A -pregnene3fl,17adiol-19-al 17-acetate (Compound No. 15) in 15 cc. of benzene and about 1 cc. was distilled to remove moisture. 0.4 g. of p-toluenesulfonic acid were added to the cooled solution, which was then allowed to stand at room temperature for 4 days. The solution was washed with sodium carbonate and water, dried and evaporated. The residue was chromatographed on 15 g. of neutral alumina. Crystallization of the fractions eluted with hexane from pentane yielded the 3-tetrahydropyranylether of 20- cycloethylenedioxy 16,8-methyl-A -pregnene-3,8,17u-diol- 19-al 17-acetate (Cpd. No. 22).

The Compounds Nos. 16 to 21, inclusive, were treated in the same manner, thus alfording respectively:

Cpd. No.

23. The 3-tetrahydropyranylether of 20-cycloethylenedioxy-A pregnen-3Bol-19-a1 24. The 3-tetrahydropyranylether of 20-cycloethylenedioxy-16a-amethyl-A -pregnen-3fl-ol-l9-al 25. The 3-tetrahydropyranylether of 20-cycloethylenedioxy,-16fi-methyl-A -pregnen-35ml-19-al 26. The 3-tetrahydr-opyranylether of ZO-cycloethylenedioxy-160:,17a-isopropylidenedioxy-A pregnen- 3,8-ol-19-a1 6 Cpd. No.Continued 27. The 3-tetrahydropyranylether of 20-cycloethylenedioxy-M-pregnene-SB,17u-diol-l9-al 17-acetate 28. The 3-tetrahydropyranylether of ZO-Cycloethylenedioxy 16a-methyl-M-pregnene-Bfl,l7a-diol l9- a1 l7-acetate Example 5 A solution of 5 g. of Compound No. 22 in 250 cc. of thiophene-free benzene was treated with 27.5 cc. of 4 N methylm-agnesium bromide in ether and the mixture refluxed with the exclusion of moisture for 3 hours. The cool-ed mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

Recrystallization from methylene chloride-hexane afforded the B-tetrahydropyratnylether of 20-cycloethylenedioxy-16B,l9-dimethyl-A -pregnene-319,l7a,l9-trio1 (Cpd. No. 29).

By the same procedure, the Compounds Nos. 23 to 28, inclusive, were converted respectively int-o:

Cpd. No.

30. The 3-tetrahydropyranylether of 20-cycloethy1- en-edioxy-l9-methyl-A -pregnene 3fi,19-diol 31. The 3-tetrahydropyranylether of 20-cyc1oethy1- enedioxy-l6a,19-diinethyl-A -pregnene-3 3,19-diol 32. The 3-tetrahydropyranylether of 20-cycloethylenedioxy-l 6B, 1 9-dimethyl-A -pregnene-35,19-diol 33. The 3-tetrahydropyranylether of 20-cycloethylenedioxy 16a, l7a-isopropylidenedioxy-l9-methyl- A -pregnene-3B,19-diol 34. The 3-tetrahydropyrany1ether of 20-cycloethylenedioxy-l9-methyl-A -pregnene 3fi,17a,19 triol 35. The 3-tetrahydropyranylether of 20-cycloethylenedioxy 16a,l9-dimethyl-A -pregnene-3B,1711,19- triol Example 6 The compounds Nos. 22 to 28, inclusive, were treated in accordance with Example 5, except that methyl magnesium bromide was substituted by ethyl magnesium bromide, thus affording respectively:

Cpd. No.-

36. The S-tetrahydropyranylether of 20-cycloethy1- ene dioxy 163 methyl-l9-ethyl-A -pregnene- 3,B,l7oc,19t1i01 37. The 3-tetrahydropyranylether of 20-cycloethylene-dioxy-19-ethyl-A -pregnene-3fi,19-diol Y 38. The 3-tetrahydropyranylether of 20-cyeloethylene dioxy 16a methyl 19 ethyl-A -pregnene- 318,19-diol 39. The 3-tetrahydropyranylether of 20-cycloethylene-dioxy 16B methyl l9 ethyl-M-pregnene- 3fi,19-diol 40. The 3-tetrahydropyranylether of 20-cycloethylene-dioxy-16tx,17a-isopropylidenedioxy l9 ethyl- A -pregnene-3B,19-diol 41. The 3-tetrahydropyranylether of 20-cycloethylene-dioxy-l 9-ethyl-A -pregnene-3/3, 1704,19-t1i0l 42. The 3-tetrahydropyranylether of 20-cycloethylene-dioxy-16u-methy1 19 ethyl A pregnene- 3fl,17ot,19-Ui01 Example. 7

The Compounds Nos. 29 to 42, inclusive, were treated in accordance with Example 2, thus affording respectively the following compounds:

43. The 3-tetrahydropyranylether of 20-cycloethylene dioxy 16 6,19-dimethyl-A -pregnene-3B,17adiol-19-one 44. The 3-tetrahydropyranylether of 20-cycloethylene-dioxy-l9-methyl-A -pregnen-3 3-ol-19-one A pregnen 35- Example The Compound No. 57 was treated in accordance with Example 9, except that acetic anhydride was substituted by propionic anhydride, thus afiording 1618,19-dimethyl- A pregnene 3'B,17oc,19 triol one 3,19 dipropionate (Cpd. No. 113).

Example 11 The Compound No. 29 was successively treated in accordance with Examples 9 and 5, thus afiording respectively: the 3-tetrahydropyrany1ether-19-acetate of 20- cycloethylene dioxy 16,9,19 dimethyl A pregnene- 3-B,17oa,19-t1'i01 (Cpd. No. 114) and the 19-acetate of 16p, 19 dimethyl A pregnene 33,17a, 19 triol 20 one (Cpd. No. 115).

Example 12 To a solution of 5 g. of 19-methyl-A -pregnene-36,170, 19-triol-20-one (Cpd. No. 62) in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. of caproic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from ether-hexane produced 19 methyl A pregnene 3fl,17a,19 triol- 20-one tricaproate (Cpd. No. 116).

Example 13 19 ethyl A pregnene 3,3,17a,19 triol 20 one (Cpd. No. 69) was successively treated in accordance with Examples 12 and 3, thus yielding respectively: 19-

ethyl A pregnene 313,170c,19 triol 20 one tricaproate (Cpd. No. 117) and 19 ethyl A pregnene 3B, 17,19 triol 20 one 17 caproate (Cpd. No. 118).

Example 14} Example 15 Compounds Nos. 119 and 120 were treated in accordance with Example 9, yielding respectively: 19-methyl- A -pregnenc-3B,16m,l7a,19-tetrol-20-one 3,16,19-triacetate (Cpd. No. 121) and 19-methyl-A -pregnene-3/8,16a,17atriol-19,20-dione 3,16-diacetate (Cpd. No. 122).

, 10 v Example 16 Compounds Nos. 119 and 120 were treated in accordance with Example 12, thus affording respectively: 19- methyl-A -pregnene-3BJ6a,17a,19-tetrol-20-one tetracaproate (Cpd. No. 123) and 19-methy1-A -pregnene-3fi,16a, 17a-triol-19,20-dione tricaproate (Cpd. No. 124). i

I claim: 1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, hydroxyl, and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T is a member of the group consisting a-hydroxy, a-hydrocarbon carboxylic acyloxy of less than 12 carbons, a-methyl and fl-methyl; T and R together are the group wherein R and R are lower alkyl groups; R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and X is a lower alkyl group.

2. 16a,19-dimethyl-A -pregnene-3[3,19 dio1-20-one.

3. 1619,19-dimethyl-A -pregnene-313,19-diol-20-one.

4. 16a,17u-isopropylidenedioxy-19-methyl-A -pregnene- 35,19-diol-20-one.

5. 16a,19-dimethyl-A pregnene-3/3,l7a,19-triol-20-one.

6. A compound of the following formula:

1.... x MN O=( l T wherein R is selected from the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T is a member of the group consisting of u-hydroxy, tit-hydrocarbon carboxylic acyloxy of less than 12 carbons, u-methyl and fi-methyl; T and R together are the group wherein R and R are lower alkyl groups; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and X is a lower alkyl group.

7. 165,19-dimethyl A pregnene 3 3,170: did-19,20- dione.

8. 16a,19 dimethyl-A -pregnen-3,8-01-19,20-dione.

11 9. 16B,19-dimethyl-A -pregnen-3fl-ol-19,20-dione. 10. 16u,17a-isopropylidenedioxy-19-methyI-A -pregnem 36-01-1 9,20-di0ne.

11. 16a,19-dimethy1- A pregnene- 3,3,17oc-diO1-19,20- dione.

12. 16a-methy1-19-ethy1-A -pregnen-3/3-01-19,20-dione.

13. 16B-methyl-19-ethyl-A -pregnen-3,6-01-19,20 dione.

14. 16a,l7a-isopropylidenedioxy-19-ethyl A -pregnen- 3fi-01-19,20-c'li0ne.

12 References Cited by theExaminer UNITED STATES PATENTS 3,067,198 12/62 Wettstein et a1. 260-23955 3,077,482 2/63 Wettstein et a1. 260397.1 3,087,940 4/63 Rubin 260397.4

LEWIS GOTTS, Primary Examiner.

MORRIS LIEBMAN, Examiner. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 